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Roflumilast in Non-CF Bronchiectasis Study

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ClinicalTrials.gov Identifier: NCT03428334
Recruitment Status : Completed
First Posted : February 9, 2018
Last Update Posted : October 1, 2019
Information provided by (Responsible Party):
James Chung-Man HO, The University of Hong Kong

Tracking Information
First Submitted Date  ICMJE January 26, 2018
First Posted Date  ICMJE February 9, 2018
Last Update Posted Date October 1, 2019
Actual Study Start Date  ICMJE May 10, 2018
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2018)
sputum leukocyte density [ Time Frame: Reduction of sputum leukocyte density in 4 weeks ]
Sputum leukocyte density is measured within 2 hours of collection by a designated technician, based on five aliquots chosen randomly from the center of a fresh specimen, which are then serially diluted with phosphate-buffered saline (PBS) and read with a light microscope and a hemocytometer
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Roflumilast in Non-CF Bronchiectasis Study
Official Title  ICMJE A 4-week Single-arm Study of Roflumilast in Stable-state Non-cystic Fibrosis Bronchiectasis
Brief Summary

This is a single-arm, open label, Phase II study of Roflumilast in stable-state non-cystic fibrosis bronchiectasis subjects.

Bronchiectasis refers to a suppurative lung condition characterized by pathological dilatation of bronchi. The predominant aetiology of bronchiectasis in the Western population is related to cystic fibrosis (CF), which is genetically determined. Bronchiectasis due to other causes are generally grouped under the term "non-CF bronchiectasis", which accounts for practically all cases that are seen commonly in Hong Kong and many other Chinese populations.

The main pathogenesis of non-CF bronchiectasis involves airway inflammation, abnormal mucus clearance and bacterial colonization, resulting in progressive airway destruction and distortion. The current treatment strategies mainly focus on targeting the key elements in the pathogenesis of non-CF bronchiectasis.

In patients with bronchiectasis, there is also neutrophilic inflammation as in COPD. It is hypothesized that roflumilast can improve airway inflammation, sputum volume and sputum inflammatory markers in patients with bronchiectasis.

This study aims to investigate the effect of short-term (4-week) treatment with roflumilast on neutrophilic airway inflammation in stable-state non-CF bronchiectasis.

Detailed Description

Apart from regular chest physiotherapy and postural drainage to help clearing mucus from bronchiectatic airways, inhalational and parenteral antibiotics have also been used to reduce the bacterial load in destroyed airways, thus controlling and preventing infective exacerbations. In recent years, accumulated evidence has suggested a central role of airway inflammation and immune dysregulation in the evolution of non-CF bronchiectasis. The classical type of airway inflammation is neutrophilic, with abundance of neutrophils in sputum, bronchoalveolar lavage fluid and bronchial biopsy from patients with non-CF bronchiectasis, even in clinically stable-state. The recruitment and trafficking of neutrophils to bronchiectatic airways are mediated via various pro-inflammatory cytokines like interleukin-1β (IL-1β), IL-8, tumour necrosis factor (TNF)-alpha and leukotriene B4 (LTB4). Investigators have also shown in an in vitro model that sputum from patients with non-CF bronchiectasis could stimulate IL-6 production from normal human bronchial epithelial cells, mediated via TNF-alpha. Recent data have suggested the involvement of Th17 immunity, in which Th17-polarized Cluster of Differentiation 4 (CD4) T cells can respond to bacteria (especially Pseudomonas aeruginosa) in bronchiectatic airways by elaboration of IL-17, leading to downstream IL-8 release from airway epithelial cells, neutrophil chemotaxis, mucus hypersecretion and formation of ectopic lymphoid follicles. This IL-17 driven pathway can further aggravate the vicious circle of key pathogenetic mechanisms in non-CF bronchiectasis. In previous studies, airway neutrophilic inflammation as indicated by sputum neutrophil count was inversely correlated with lung function (forced expiratory volume in 1 second, FEV1) and directly with duration of disease and severity (Bronchiectasis Severity Score, BSI) in stable non-CF bronchiectasis. Investigators have also demonstrated that sputum elastase, released from airway neutrophils, significantly correlated with 24-hour sputum volume, number of bronchiectatic lobes, percent predicted FEV1, and sputum leukocyte count in stable-state bronchiectasis. Patients with non-CF bronchiectasis harbouring Pseudomonas aeruginosa showed greater sputum neutrophilia and volume, with lower FEV1 and FEV1/forced vital capacity (FVC) ratio in previous studies from our group and others.

This study aims to investigate the extent of airway inflammation in non-CF bronchiectasis is indicated by sputum leukocyte density (primary outcome measure), pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, LTB4 and IL-17) and neutrophil elastase. Investigators hypothesize that 4-week treatment of roflumilast in stable-state non-CF bronchiectasis can result in: (1) reduction in sputum leukocyte density (primary hypothesis); (2) reduction in sputum pro-inflammatory cytokines (IL-1β, IL-8, TNF-alpha, and IL-17) and LTB4; (3) reduction in sputum neutrophil elastase; (4) reduction in 24-h sputum volume; (5) no change in sputum bacterial colonization, load and microbiome.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-cystic Fibrosis Bronchiectasis
Intervention  ICMJE Drug: Oral roflumilast
Roflumilast, a phosphodiesterase 4 (PDE4) inhibitor is approved worldwide (including Hong Kong) for treatment of severe chronic obstructive pulmonary disease (COPD) with frequent exacerbations. Roflumilast has been shown to have anti-inflammatory effect in patients with COPD, with significant reduction of sputum absolute neutrophil count, IL-8 and neutrophil elastase compared with placebo treatment. Roflumilast can also improve the lung function parameters in patients with COPD and reduce the rate of moderate-to-severe exacerbations.
Other Name: Daxas
Study Arms  ICMJE Experimental: Oral roflumilast
oral roflumilast 500 microgram daily for 4 weeks
Intervention: Drug: Oral roflumilast
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 8, 2018)
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE August 31, 2019
Actual Primary Completion Date August 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Aged 18 years or above, male or female.
  2. Never-smokers or those who have smoked less than 100 cigarettes in their lifetime.
  3. Confirmed diagnosis of non-CF bronchiectasis based on high-resolution computed tomography (HRCT) scan.
  4. Significant sputum production (≥ 10 ml per day).
  5. In stable-state bronchiectasis with no change in regular medications (e.g. inhaled steroid, macrolide) or exacerbations in the past 3 months.
  6. Written informed consent obtained.

Exclusion Criteria:

  1. Eversmokers (≥ 100 cigarettes in their lifetime).
  2. Known chronic obstructive pulmonary disease or asthma.
  3. Moderate to severe liver impairment (Child-Pugh B or C).
  4. Known psychiatric illness with increased suicidal risks.
  5. Body-mass index below 20 kg/m2.
  6. Concomitant use of strong cytochrome P450 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin).
  7. Patients who are hypersensitive to roflumilast or its constituents.
  8. Pregnant or lactating women.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Hong Kong
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03428334
Other Study ID Numbers  ICMJE ROF2017_v1
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party James Chung-Man HO, The University of Hong Kong
Original Responsible Party Same as current
Current Study Sponsor  ICMJE The University of Hong Kong
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James CM Ho, MD The University of Hong Kong
PRS Account The University of Hong Kong
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP